This invention relates to 10-(1,2-propadienyl) steroids which are irreversible inhibitors of aromatase enzymes. Processes for preparing these steroids and methods of using them are also provided.
Divergent sex hormones which are synthesized by the gonads and, to a lesser extent, by the adrenals, are primarily responsible for the expression of secondary sex characteristics of either males or females. These steroids are regulated by a number of enzymes. The enzyme aromatase is the rate-limiting enzyme in the conversion of androgens (male hormones) to estrogens (female hormones). The non-reversible conversion of androgens to estrogens involves the oxidation and elimination of the methyl group from C10 as formic acid. The 1.beta. and 2.beta. hydrogens from C1 and C2 are also lost to produce the aromatic A-ring of estrogens. The androgens, testosterone ##STR2## and androstenedione, or the estrogens, estradiol and estrone, can be interconverted by 17.beta.-hydroxy-steroid dehydrogenase (FIG. 1). The regulation of the conversion of androgen to estrogen or the inhibition of this conversion has therapeutic utility in regulating clinical conditions which are potentiated by the presence of estrogens.
There is substantial clinical evidence that many tumor types are associated with elevated estrogen production. Ovariectomy, adrenalectomy and hypophysectomy are commonly employed in patients with breast cancer as a means of reducing the amount of estrogen. Non-surgical procedures include treatments with high levels of steroids, anti-estrogens and inhibitors of steroidal enzymatic pathways. Treatment with anti-estrogens results in about one-third of the patients obtaining objective tumor regressions. Adrenalectomy will cause regression of breast cancer in postmenopausal women with hormonal-dependent tumors, presumably as the result of reduction in available estrogen derived from androstenedione, whose source is primarily from the adrenals. Growth of several lines of breast cancer cells have been shown to be estrogen-dependent, and can be inhibited by compounds which antagonize estrogen action.
Inhibitors of estrogen biosynthesis have been identified using microsomal enzyme preparations from human placenta. Aromatase inhibitors such as 4-hydroxy- and 4-acetoxy-androstene-3,17-dione, aminoglutethimide and testololactone are capable of blocking the aromatization of androgens to estrogens and can effectively prevent the biologically active estrogens from reaching endocrine tumors or reduce estrogen biosynthesis in those tumors capable of endogenous estrogen synthesis, thereby producing remissions of metastatic breast cancer.
Endometrial cancer has been related to the presence of excessive endogenous or exogenous estrogen. Gonadal and trophoblastic tumors cause somatic hyperestrogenization, which results in varying degrees of feminization in males. In females, the symptoms depend upon the age of the patient, and may range from precocious pseudopuberty to abnormalities of menses to postmenopausal bleeding. Aromatase inhibitors can be used in adjunctive therapy in the conservative management of patients with such tumors, since they will reduce the somatic expression of increased estrogen biosynthesis. Aromatase inhibitors have been administered for treatment of hyperestrogenemia in conditions such as gynecomastia, and have resulted in clinical improvement.
Hyperestrogenemia has been suggested to precede myocardial infarction. Reduction in peripheral aromatization of androgens by administration of aromatase inhibitors could therefore be useful for treatment of individuals having a high potential risk of myocardial infarctions.
Aromatase inhibitors have been shown to be effective in treating male infertility, and in preventing estrogen production required for ovulation in females. Since estrogen synthesis is required for implantation of fertilized ova in many species, post-coital administration of aromatase inhibitors has the potential to regulate fertility, particularly in domestic pets and wildlife. In particular, suppression of both male and female rodent reproduction could be effected during controlled mating programs using aromatase inhibitors.